Remedies for cirrhosis

ABSTRACT

It is provided that type-X sPLA 2  inhibitors are useful in preventing or treating hepatocirrhosis.

TECHNICAL FIELD

[0001] The present invention relates to a composition for the preventionor treatment of hepatocirrhosis which contains an inhibitor againsttype-X sPLA₂ (secretary PLA₂) as an active ingredient.

BACKGROUND ART

[0002] sPLA₂ inhibitors are disclosed in EP-620214 (JP Laid-Open(Tokukai) No. 95/010838, U.S. Pat. No. 5,578,634). And it is describedin U.S. Pat. No. 5,478,857 (WO95/17183, JP Laid-Open (Tokuhyo) No.97/507069) that type-II sPLA₂ inhibitors are effective for apoptosisassociated disease. However, the above-mentioned documents do notdescribe compounds having inhibitory activities against type-X sPLA₂ orthat type-X sPLA₂ inhibitors are effective for the treatment ofhepatocirrhosis.

DISCLOSURE OF INVENTION

[0003] The inventors of the present invention examined the expression oftype-X sPLA₂ in various kinds of human pathological tissues withanti-type-X sPLA₂ antibody. They found the elevated expression of type-XsPLA₂ in pseudolobule in the liver prepared from patients ofhepatocirrhosis.

[0004] The immunohistochemical analysis of each tissue was performed asfollows. At first, anti-human type-X sPLA₂ antibody was added to theslides prepared from normal adult liver tissues or liver tissuesprepared from patients of hepatocirrhosis and incubated for severalhours. Next, in order to examine the expression of type-X sPLA₂ in thetissues, the expression of type-X sPLA₂ was visualized by using themethods such as the immunohistochemical labeling to detect the type-XsPLA₂ signals. Consequently, the type-X sPLA₂ signals were detected inthe slides prepared from liver tissues prepared from patients ofhepatocirrhosis, suggesting that the expression of type-X sPLA₂ iselevated in liver tissues prepared from patients of hepatocirrhosis.

[0005] In addition, the inventors of the present invention performed theexperiments for neutralization of type-X sPLA₂ signals. Precisely,before the addition of anti-human type-X sPLA₂ antibody to the slides,the slides were incubated with the purified type-X sPLA₂ protein forseveral hours. Hereafter, the slides were processed as the sameprocedures as described above to examine the type-X sPLA₂ signals.Consequently, the type-X sPLA₂ signals were disappeared in the slidesprepared from liver tissues.

[0006] Thus, the elevated expression of type-X sPLA₂ was confirmed inliver tissues prepared from patients of hepatocirrhosis and theinventors of the present invention achieved the following presentinvention.

[0007] That is to say, the present invention relates to I) a compositionfor prevention or treatment of hepatocirrhosis which contains a type-XsPLA₂ inhibitor as an active ingredient.

[0008] In more detail, the present invention relates to the followingII) to XIII).

[0009] II) A composition for prevention or treatment of hepatocirrhosiswhich contains as an active ingredient a compound represented by theformula (I):

[0010]  wherein Ring A is represented by the formula (a) to (d):

[0011]  wherein R¹ and R² are each independently hydrogen atom,non-interfering substituent, or -(L¹)-(acidic group) wherein L¹ is anacid linker having an acid linker length of 1 to 5, provided that one ofthe R¹ and R² is -(L¹)-(acidic group);

[0012] R³ and R⁴ are each independently hydrogen atom, non-interferingsubstituent, carbocyclic group, carbocyclic group substituted with anon-interfering substituent(s), heterocyclic group, or heterocyclicgroup substituted by a non-interfering substituent(s); and

[0013] —B— is represented by the formula (e) to (h):

[0014]  wherein R⁵ is (j) C1 to C20 alkyl, C2 to C20 alkenyl, C2 to C20alkynyl, carbocyclic group, or heterocyclic group, (k) the grouprepresented by (j) each substituted independently with at least onegroup selected from non-interfering substituents, or -(L²)—R⁸ wherein L²is a divalent linking group of 1 to 18 atom(s) selected from hydrogenatom(s), nitrogen atom(s), carbon atom(s), oxygen atom(s), and sulfuratom(s), and

[0015] R⁸ is a group selected from the groups (j) and (k);

[0016] R⁶ is hydrogen atom, halogen, C1 to C3 alkyl, C3 to C4cycloalkyl, C3 to C4 cycloalkenyl, C1 to C3 alkyloxy, or C1 to C3alkylthio;

[0017] R⁷ is hydrogen atom or non-interfering substituent;

[0018] R^(A) is represented by the formula:

[0019]  wherein R⁹ and R¹⁰ are each independently hydrogen atom, C1 toC3 alkyl, or halogen;

[0020] X and Y are each independently oxygen atom or sulfur atom; and

[0021] Z is —NH₂ or —NHNH₂;

[0022] RB is —CONH₂ or —CONHNH₂; and,

[0023] Ring D is cyclohexene ring or benzene ring;

[0024]  provided that Ring A is (b), (c), or (d) when —B— is (e) or (f),

[0025]  a prodrug thereof, its pharmaceutically acceptable salt, or itssolvate.

[0026] III) A composition for prevention or treatment of hepatocirrhosiswhich contains a compound, a prodrug thereof, its pharmaceuticallyacceptable salt, or its solvate as described in II) as an activeingredient, wherein R¹ is hydrogen atom or -(L³)-R¹¹ wherein L³ is—OCH₂—, —SCH₂—, —NH—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, or —O—CH(CH₂CH₂C₆H₅)—;R¹¹ is —COOH, —CONHSO₂C₆H₅, —SO₃H, or —P(O)(OH)₂; and

[0027] R² is hydrogen atom or -(L⁴)—R¹² wherein L⁴ is represented by theformula:

[0028]  wherein R¹³ and R¹⁴ are each independently hydrogen atom, C1 toC₁₀ alkyl, C1 to C10 aralkyl, carboxy, alkyloxycarbonyl, or halogen; R¹²is —COOH, —SO₃H, or —P(O)(OH)₂, provided R¹ and R² are not hydrogen atomat the same time.

[0029] IV) A composition for prevention or treatment of hepatocirrhosiswhich contains a compound, a prodrug thereof, its pharmaceuticallyacceptable salt, or its solvate as described in II) or III) as an activeingredient, wherein R³ is hydrogen atom, C1 to C6 alkyl, C3 to C6cycloalkyl, aryl, or a heterocyclic group and R⁴ is hydrogen atom orhalogen.

[0030] V) A composition for prevention or treatment of hepatocirrhosiswhich contains a compound, a prodrug thereof, its pharmaceuticallyacceptable salt, or its solvate as described in any one of II) to IV) asan active ingredient, wherein R⁵ is —(CH₂)₁₋₆—R¹⁵ wherein R¹⁵ isrepresented by the formula:

[0031]  wherein b, d, f, h, j, m, and o are independently an integerfrom 0 to 2; R¹⁶ and R¹⁷ are each independently halogen, C1 to C10alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryloxy, or C1 to C10haloalkyl; a is oxygen atom or sulfur atom; β is —CH₂— or —(CH₂)₂—; γ isoxygen atom or sulfur atom; c, i, and p are independently an integerfrom 0 to 5; e is an integer from 0 to 7; g is an integer from 0 to 4; kand n are each independently an integer from 0 to 3.

[0032] VI) A composition for prevention or treatment of hepatocirrhosiswhich contains a compound, a prodrug thereof, its pharmaceuticallyacceptable salt, or its solvate as described in V) as an activeingredient, wherein R⁵ is —CH₂—R¹⁸ wherein R¹⁸ is represented by theformula:

[0033]  wherein β is —CH₂— or —(CH₂)₂—; R¹⁹ is hydrogen atom, C1 to C3alkyl, or halogen; E is a bond, —CH₂— or —O—.

[0034] VII) A composition for prevention or treatment of hepatocirrhosiswhich contains a compound, a prodrug thereof, its pharmaceuticallyacceptable salt, or its solvate as described in any one of II) to VI) asan active ingredient, wherein R¹ is —OCH₂COOH.

[0035] VIII) A composition for prevention or treatment ofhepatocirrhosis which contains a compound, a prodrug thereof, itspharmaceutically acceptable salt, or its solvate as described in any oneof II) to VII) as an active ingredient, wherein R² is hydrogen atom.

[0036] IX) A composition for prevention or treatment of hepatocirrhosiswhich contains a compound, a prodrug thereof, its pharmaceuticallyacceptable salt, or its solvate as described in any one of II) to VIII)as an active ingredient, wherein R⁶ is C1 to C3 alkyl.

[0037] X) A composition for prevention or treatment of hepatocirrhosiswhich contains a compound, a prodrug thereof, its pharmaceuticallyacceptable salt, or its solvate as described in any one of II) to IX) asan active ingredient, wherein RA is —CH₂CONH₂ or —COCONH₂.

[0038] XI) A composition for prevention or treatment of hepatocirrhosiswhich contains a compound as an active ingredient represented by theformula:

[0039]  a prodrug thereof, its pharmaceutically acceptable salt, or itssolvate.

[0040] XII) Use of a type-X sPLA₂ inhibitor for the preparation of amedicament for the treatment of hepatocirrhosis.

[0041] XIII) Use as described in XII) wherein the type-X sPLA₂ inhibitoris the compound described in any one of II) to XI).

[0042] XIV) A method of treating a mammal, including a human, toalleviate the pathological effects of hepatocirrhosis, which comprisesadministration to said mammal of a type-X sPLA₂ inhibitor in apharmaceutically effective amount.

[0043] XV) A method as described in XIV) wherein the type-X sPLA₂inhibitor is the compound described in any one of II) to XI).

[0044] The present invention is illustrated in detail as follows

[0045] Type-X sPLA₂ inhibitors mean compounds which have an inhibitoryactivity against type-X sPLA₂ and other optional activities such asinhibitory activities against other enzymes or affinities for anyreceptors. Namely, the inhibitors include any compound having strongeractivities against type-X sPLA₂ than that having no such activities inthe evaluation test therefore. Especially, type-X sPLA₂ selectiveinhibitors are preferred as type-X sPLA₂ inhibitors of the presentinvention. For example, compounds whose IC₅₀ values against type-X sPLA₂are 1 μM or less in the experiment of Example 2 are preferred. Compoundshaving IC₅₀ values 100 nM or less are more preferred.

[0046] A compound having type-X sPLA₂ inhibitory activities, having oneor more of chiral center(s), may exist as an optically active member.Likewise, a compound containing alkenyl or alkenylene, may be a cis- ortrans-isomer. Mixtures of R- and S-isomers as well as of cis- andtrans-isomers, and mixtures of R- and S-isomers containing a racemicmixture are included in the scope of the present invention. Anasymmetric carbon atom may exist also in a substituent such as alkylgroup. All such isomers and mixtures are included in the presentinvention. A specified stereoisomer can be manufactured by subjecting tostereospecific reaction well known to those skilled in the art applyinga previously separated starting material having an asymmetrical centeror by preparing a mixture of stereoisomers and separating the mixture inaccordance with a well-known manner.

[0047] Prodrug is a derivative of a compound with type-X sPLA₂inhibitory activities, having a group which can be decomposed chemicallyor metabolically, and becoming pharmaceutically active by solvolysis orin vivo under a physiological condition. Although the derivative, acidderivative or basic derivative, exhibits activity, an acid derivative ismore advantageous in solubility, tissue affinity, and release control inmammal organism (Bungard, H., Design of Prodrugs, pp. 7-9, 21-24,Elsevier, Amsterdam, 1985). For instance, prodrugs, including an acidderivative such as an ester which is prepared by reacting a basal acidcompound with a suitable alcohol, or an amide which is prepared byreacting a basal acid compound with a suitable amine, are well known tothose skilled in the art. Simple aliphatic or aromatic esters derivedfrom acid groups contained in the compounds according to the presentinvention are preferable prodrugs. Particularly preferred esters asprodrugs are C1-C6 alkylester (e.g. methyl ester, ethyl ester). Doubleester such as (acyloxy)alkyl ester or ((alkyloxycarbonyl)oxy)-alkylester type prodrugs may be optionally manufactured.

[0048] When a compound having type-X sPLA₂ inhibitory activities has anacidic or basic functional group, a variety of salts having a higherwater solubility and more physiologically suitable properties than thoseof the original compound can be formed. An example of typicalpharmaceutically acceptable salts includes salts with alkali metal andalkaline earth metal such as lithium, sodium, potassium, magnesium,aluminum and the like, but it is to be noted that such pharmaceuticallyacceptable salts are not limited thereto. A salt is easily manufacturedfrom a free acid by either treating an acid in a solution with a base,or allowing an acid to be in contact with an ion exchange resin.Addition salts of the compounds having type-X sPLA₂ inhibitoryactivities with relatively non-toxic inorganic bases and organic bases,for example, amine cation, ammonium, and quaternary ammonium derivedfrom nitrogenous bases having a basicity sufficient for forming a saltof the compounds of the present invention are included in the definitionof “pharmaceutically acceptable salts”. (e.g., S. M. Berge et al.,“Pharmaceutical Salts, “J. Phar. Sci., 66, 1-19 (1977)). Furthermore,basic groups of a compound having type-X sPLA₂ inhibitory activities arereacted with a suitable organic or inorganic acid to form salts such asacetates, benzenesulfonates, benzoates, bicarbonates, bisulfates,bitartrates, borates, bromide s, camsylates, carbonates, chlorides,clavulanates, citrates, edetates, edisylates, estolates, esylates,fluorides, fumarates, gluceptates, gluconates, glutamates,glycolylarsanilates, hexylresorcinates, hydroxynaphthoates, iodides,isothionates, lactates, lactobionates, laurates, malates, maleates,mandelates, mesylates, methylbromides, methylnitrates, methylsulfates,mucates, napsylates, nitrates, oleates, oxalates, palmitates,pantothenates, phosphates, polygalacturonates, salicylates, stearates,subacetates, succinates, tannates, tartrates, tosylate s,trifluoroacetates, trifluoromethanesulfonates, valerates and the like.

[0049] The solvate includes solvates with organic solvents and/orhydrates. In case of forming a hydrate, a questioned compound may becoordinated with a suitable number of water molecules.

[0050] The term “pharmaceutically acceptable” means that carriers,diluents, or additives are compatible with other ingredients in aformulation and are not harmful for recipients.

[0051] “Hepatocirrhosis” is a progressive hepatopathy which compriseswide suffer damage of liver parenchymal cell accompanied withreconstruct of hepatic lobule structure, causes often jaundie, portalhypeternsion, or hydroperitoneum, and finally hepatargy. Based on theexperiments, the inventors of the present invention confirmed theelevated expression of type X sPLA₂ in pseudoacinus of hepatocytesderived from patient of hepatocirrhosis. Especially, the invention isuseful for prevention or treatment of hepatocirrhosis.

[0052] In the present specification, the term “alkyl” employed alone orin combination with other terms means a straight- or branched chainmonovalent hydrocarbon group having a specified number of carbon atoms.An example of the alkyl includes methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl,n-tetradecanyl, n-pentadecanyl, n-hexadecanyl, n-heptadecanyl,n-octadecanyl, n-nonadecanyl, n-eicosanyl and the like.

[0053] The term “alkenyl” employed alone or in combination with otherterms in the present specification means a straight- or branched chainmonovalent hydrocarbon group having a specified number of carbon atomsand at least one double bond. An example of the alkenyl includes vinyl,allyl, propenyl, crotonyl, isopentenyl, a variety of butenyl isomers andthe like.

[0054] The term “alkynyl” used in the present specification means astraight or branched chain monovalent hydrocarbon group having aspecified number of carbon atoms and at least one triple bond. Thealkynyl may contain (a) double bond(s). An example of the alkynylincludes ethynyl, propynyl, 6-heptynyl, 7-octynyl, 8-nonynyl and thelike.

[0055] The term “carbocyclic group” used in the present specificationmeans a group derived from a saturated or unsaturated, substituted orunsubstituted 5 to 14 membered, preferably 5 to 10 membered, and morepreferably 5 to 7 membered organic nucleus whose ring forming atoms(other than hydrogen atoms) are solely carbon atoms. A group containingtwo to three of the carbocyclic group is also included in the abovestated group. An example of typical carbocyclic groups includescycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl, cycloalkenyl such as cyclobutylenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl, phenyl,naphthyl, norbornyl, bicycloheptadienyl, indenyl, stilbenyl,terphenylyl, phenylcyclohexenyl, acenaphthyl, anthryl, biphenylyl,bibenzyl, and a phenylalkylphenyl derivative represented by the formula(II):

[0056] Phenyl, cycloalkyl or the like is preferred as a carbocyclicgroups in the R³ and R⁴.

[0057] The term “heterocyclic group” used in the present specificationmeans a group derived from monocyclic or polycyclic, saturated orunsaturated, substituted or unsubstituted heterocyclic nucleus having 5to 14 ring atoms and containing 1 to 3 hetero atoms selected from thegroup consisting of nitrogen atom, oxygen atom, and sulfur atom. Anexample of the heterocyclic group includes pyridyl, pyrrolyl, furyl,benzofuryl, thienyl, benzothienyl, pyrazolyl, imidazolyl,phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl,thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl,benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl,imidazo[1,2-a]pyridinyl, benzotriazolyl, anthranilyl,1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, puridinyl,dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl,phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl, phthalazinyl,quinazolinyl, quinoxalinyl, and the like.

[0058] Furyl, thienyl or the like is preferred as a heterocyclic groupin the R³ and R⁴.

[0059] Preferred carbocyclic and heterocyclic groups in R⁵ representedby the formula:

[0060] wherein h is an integer from 0 to 2, R¹⁶ and R¹⁷ are eachindependently halogen, C1-C10 alkyl, C1-C10 alkyloxy, C1-C10 alkylthio,aryloxy, or C1-C10 haloalkyl, α is oxygen atom or sulfur atom, β is—CH₂— or —(CH₂)₂—, γ is oxygen atom or sulfur atom, c, i, and p are eachindependently an integer from 0 to 5, e is an integer from 0 to 7, g isan integer from 0 to 4, k and n are each independently an integer from 0to 3. When the above c, e, g, i, k, n, and/or p are 2 or more, a pluralnumber of R¹⁶ or R¹⁷ may be different from one another. When R¹⁶ is asubstituent on the naphthyl group, the substituent may be substituted atany arbitrary position on the naphthyl group.

[0061] A more preferable example includes a group represented by theformula:

[0062] wherein R¹⁹ is hydrogen atom, C1-C3 alkyl or halogen; E is abond, —CH₂—, or —O—; β is —CH₂— or —(CH₂)₂— as defined above.

[0063] The above-mentioned “carbocyclic ring” C1-C3 alkyl and theabove-mentioned “heterocyclic ring” C₁-C₃ alkyl, or the like ispreferred as a group in the R⁵.

[0064] The term “non-interfering substituent” in the presentspecification means a group suitable for substitution of the abovementioned “carbocyclic group”, “heterocyclic group”, and basic skeleton.An example of the non-interfering substituents includes C1-C10 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl such as benzyl andphenethyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl,tolyl, xylyl, biphenylyl, C1-C10 alkyloxy, C1-C6 alkyloxy C1-C6 alkylsuch as methyloxymethyl, ethyloxymethyl, methyloxyethyl, andethyloxyethyl, C1-C6 alkyloxy C1-C6 alkyloxy such as methyloxymethyloxyand methyloxyethyloxy, C1-C6 alkylcarbonyl such as methylcarbonyl andethylcarbonyl, C1-C6 alkylcarbonylamino such as methylcarbonylamino andethylcarbonylamino, C1-C6 alkyloxyamino such as methyloxyamino andethyloxyamino, C1-C6 alkyloxyaminocarbonyl such asmethyloxyaminocarbonyl and ethyloxyaminocarbonyl, mono or di C1-C6alkylamino such as methylamino, ethylamino, dimethylamino, andethylmethylamino, C1-C10 alkylthio, C1-C6 alkylthiocarbonyl such asmethylthiocarbonyl and ethylthiocarbonyl, C1-C6 alkylsulfinyl such asmethylsulfinyl and ethylsulfinyl, C1-C6 alkylsulfonyl such asmethylsulfonyl and ethylsulfonyl, C2-C6 haloalkyloxy such as2-chloroethyloxy and 2-bromoethyloxy, C1-C6 haloalkylsulfonyl such aschloromethylsulfonyl and bromomethylsulfonyl, C1-C10 haloalkyl, C1-C6hydroxyalkyl such as hydroxymethyl and hydroxyethyl, C1-C6alkyloxycarbonyl such as methyloxycarbonyl and ethyloxycarbonyl,—(CH₂)₁₋₈—O—(C1-C6 alkyl), benzyloxy, aryloxy such as phenyloxy,arylthio such as phenylthio, —(CONHSO₂R²⁰) wherein R²⁰ is C1-C6 alkyl oraryl, —CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkoxy,—(CH₂)₁₋₈—COOH such as carboxymethyl, carboxyethyl, and carboxypropyl,cyano, cyanoguanidino, guanidino, hydrazide, hydrazino, hydroxy,hydroxyamino, nitro, phosphono, —SO₃H, thioacetal, thiocarbonyl, C1-C6carbonyl, a carbocyclic group, a heterocyclic group and the like. Theseare optionally substituted with one or more substituents selected fromthe group consisting of C1-C6 alkyl, C1-C6 alkyloxy, C2-C6 haloalkyloxy,C1-C6 haloalkyl, and halogen.

[0065] Preferable are halogen, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6alkylthio, and C1-C6 haloalkyl as the “non-interfering substituent” of“substituted with non-interfering substituent” in the R³, R⁴, and R⁵.More preferable are halogen, C1-C3 alkyl, C1-C3 alkyloxy, C1-C3alkylthio, and C1-C3 haloalkyl.

[0066] Preferable are C1-C6 alkyl, aralkyl, C1-C6 alkyloxy, C1-C6alkylthio, C1-C6 hydroxyalkyl, C2-C6 haloalkyloxy, halogen, carboxy,C1-C6 alkyloxycarbonyl, aryloxy, arylthio, a carbocyclic group, and aheterocyclic group as the “non-interfering substituent” in the R¹, R²,R³, R⁴, and R⁷. More preferable are C1-C6 alkyl, aralkyl, carboxy, C1-C6hydroxyalkyl, phenyl, and C1-C6 alkyloxycarbonyl.

[0067] The term “halogen” in the present specification means fluorine,chlorine, bromine, and iodine.

[0068] The term “cycloalkyl” in the present specification means amonovalent cyclic hydrocarbon group having a specified number of carbonatoms. An example of the cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0069] The term “cycloalkenyl” in the present specification means amonovalent cyclic hydrocarbon group having a specified number of carbonatoms and at least one double bond(s). An example of the cycloalkenylincludes 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl,2-cyclobutenyl and the like.

[0070] In the present specification, an example of “alkyloxy” includesmethyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy,n-hexyloxy and the like.

[0071] In the present specification, an example of “alkylthio” includesmethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,n-pentylthio, n-hexylthio and the like.

[0072] The term “acidic group” in the present specification means anorganic group functioning as a proton donor capable of hydrogen bondingwhen attached to a basic skeleton through a suitable linking atom(hereinafter defined as “acid linker”). An example of the acidic groupincludes a group represented by the formula:

[0073] wherein R²¹ is hydrogen atom, a metal, or C1-C10 alkyl; each R²²is independently hydrogen atom or C1-C10 alkyl, provided that at leastone of R²¹ or R²² is hydrogen atom in case of an acidic group havingboth R²¹ and R²². Preferable is —COOH, —SO₃H, —CONHSO₂C₆H₅, orP(O)(OH)₂. More preferable is —COOH.

[0074] The term “acid linker” in the present specification means adivalent linking group represented by a symbol -(L¹)-, and it functionsto join a basic skeleton to an “acidic group” in the generalrelationship. An example of it includes a group represented by theformula:

[0075] wherein M is —CH₂—, —O—, —N(R²⁵)—, or —S— wherein R²” and R²⁴ areeach independently hydrogen atom, C1-C10 alkyl, aryl, aralkyl, carboxy,or halogens and a group represented by the formula:

[0076] wherein R¹³ and R¹⁴ are each independently hydrogen atom, C1-C10alkyl, C1-C10 aralkyl, carboxy, alkyloxycarbonyl, or halogen. Preferableare —O—CH₂—, S—CH₂—, —N(R²⁵)—CH₂—, —CH₂—CH₂—, —O—CH(CH₃)—, or—O—CH((CH₂)₂C₆H₅)— wherein R²⁵ is C1-C6 alkyl. More preferable is—O—CH₂— or —S—CH₂—.

[0077] In the present specification, the term “acid linker length” meansthe number of atoms (except for hydrogen atoms) in the shortest chain ofa linking group -(L¹)- which connects a basic skeleton with the “acidicgroup”. The presence of a carbocyclic ring in -(L¹)- counts as thenumber of atoms approximately equivalent to the calculated diameter ofthe carbocyclic ring. Thus, a benzene and cyclohexane ring in the acidlinker counts as two atoms in calculating the length of -(L¹)-. Apreferable length is 2 to 3.

[0078] The term “haloalkyl” in the present specification means theaforementioned “alkyl” substituted with the aforementioned “halogen” atarbitrary position(s). An example of the haloalkyl includeschloromethyl, trifluoromethyl, 2-chloromethyl, 2-bromomethyl and thelike.

[0079] The term “hydroxyalkyl” in the present specification means theaforementioned “alkyl” substituted with hydroxy at arbitraryposition(s). An example of the hydroxyalkyl includes hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl and the like. In this case,hydroxymethyl is preferable.

[0080] In the present specification, the term “haloalkyl” in“haloalkyloxy” is the same as defined above. An example of it includes2-chloroethyloxy, 2-trifluoroethyloxy, 2-chloroethyloxy and the like.

[0081] The term “aryl” in the present specification means a monocyclicor condensed cyclic aromatic hydrocarbon. An example of the arylincludes phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like.Particularly, phenyl and 1-naphthyl are preferred.

[0082] The term “aralkyl” in the present specification means a groupwherein the aforementioned “alkyl” is substituted with theabove-mentioned “aryl”. Such aryl may have a bond at any substitutableposition. An example of it includes benzyl, phenethyl, phenylpropyl suchas 3-phenylpropyl, naphthylmethyl such as 1-naphthylmethyl and the like.

[0083] An example of the “alkyloxycarbonyl” in the present specificationincludes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl andthe like.

[0084] An example of the “aryloxy” in the present specification includesphenyloxy and the like.

[0085] An example of the “arylthio” in the present specificationincludes phenylthio and the like.

[0086] The term “halophenyl” in the present specification means phenylsubstituted with the aforementioned “halogen” at one or moreposition(s). An example of the halophenyl includes fluorophenyl,chlorophenyl, bromophenyl, iodophenyl, difluorophenyl, dichlorophenyl,dibromophenyl, trifluorophenyl, trichlorophenyl, tribromophenyl,chlorofluorophenyl, bromochlorophenyl, and the like.

[0087] The term “cyclohexene ring “of D ring in the presentspecification means a cyclohexene ring having only one double bond atthe condensation part with the adjacent ring.

[0088] Preferable combinations of “A ring” and “—B—” are represented bythe following (m)-(r):

[0089] Particularly, combinations represented by (m)-(p) are preferred.

[0090] Furthermore, compounds represented by formula (1) to (19) aremost preferred.

BEST MODE FOR CARRYING OUT THE INVENTION

[0091] The present invention relates to the prevention or treatment ofAlzheimer's disease by a type-X sPLA₂ inhibitor. The type-X sPLA₂inhibitor may be known one and selected from sPLA2 inhibitors, forexample, compounds described in EP-620214 (JP Laid-Open (Tokukai) No.95/010838, U.S. Pat. No. 5,578,634), EP-620215 (JP Laid-Open (Tokukai)No. 95/025850, U.S. Pat. No. 5,684,034), EP-675110 (JP Laid-Open(Tokukai) No. 95/285933, U.S. Pat. No. 5,654,326), WO 96/03120 (JPLaid-Open No. 98/505336), WO 96/03376 (JP Laid-Open No. 98/503208, U.S.Pat. No. 5,641,800), WO 96/03383 (JP Laid-Open No. 98/505584), WO97/21664 (EP-779271), WO 97/21716 (EP-779273), WO 98/18464 (EP839806),WO98/24437 (EP846687), WO98/24756, WO98/24794, WO98/25609, WO99/51605,WO99/59999 and the like, or parabromophenacyl-bromide, mepacrine,manoalide, thielocin A₁ and the like.

[0092] As another type-X sPLA₂ inhibitor, can be used the compoundsrepresented in PCT/JP00/07024 by the formula:

[0093] wherein R¹, R², R³, and R⁴ are each independently hydrogen atom,a non-interfering substituent(s) and the like, R⁵ is carbocyclic groups,heterocyclic groups, R⁶ is hydrogen atom, C1-C3 alkyl and the like, RAis —COCONH₂ and the like, RB is —CONH₂, and the like.

[0094] Further, compounds identified as type-X sPLA₂ inhibitors by thefollowing procedure and the like may be used in the present invention.The effect as the composition of the present invention is examined asfollows.

[0095] At first, a cell expressing human type-X sPLA₂ is prepared. Thatis, cDNA sequence encoding human type-X sPLA₂ (Cupillard et al., J.Biol. Chem, 1997, 272, 15745-15752) is inserted into an expressionvector for mammalian cells. The obtained expression vector istransfected into the host cell and the cell stably expressing humantype-X sPLA₂ is obtained. The transfected cell is cultured in medium andits culture supernatant is used for the measurement of each enzymeactivity.

[0096] (Inhibition Test)

[0097] In order to identify and evaluate an inhibitor of type-X sPLA₂,the following chromogenic assay is utilized. A general explanation forthis assay is described in “Analysis of Human Synovial FluidPhospholipase A₂ on Short Chain Phosphatidylcholine-Mixed Micelles:Development of a Spectrophotometric Assay Suitable for a MicortiterplateReader” (Analytical Biochemistry, 204, pp 190-197, 1992 by Laure. J.Reynolds. Lori L. Hughes and Edward A. Dennis.

[0098] Several kinds of the compounds represented by the formula (I) canbe synthesized in accordance with the methods described inPCT/JP00/07024, EP-620214 (JP Laid-Open (Tokukai) No. 95/010838, U.S.Pat. No. 5,578,634), EP-620215 (JP Laid-Open (Tokukai) No. 95/025850,U.S. Pat. No. 5,684,034), EP-675110 (JP Laid-Open (Tokukai) No.95/285933, U.S. Pat. No. 5,654,326), WO 96/03120 (JP Laid-Open No.98/505336), WO 96/03383 (JP Laid-Open No. 98/505584), WO 98/18464(EP839806), WO99/51605, WO99/59999 and the like.

[0099] The composition for treatment or prevention in the presentinvention may be administered to a patient through a variety of routesincluding oral, aerosol, rectal, percutaneous, subcutaneous,intravenous, intramuscular, and nasal routes. A formulation according tothe present invention may be manufactured by combining (for example,admixing) a curatively effective amount of a compound of the presentinvention with a pharmaceutically acceptable carrier or diluent. Theformulation of the present invention may be manufactured with the use ofwell-known and easily available ingredients in accordance with a knownmethod.

[0100] In case of manufacturing a composition of the present invention,active ingredients are admixed, or diluted with a carrier, or they arecontained in a carrier in the form of capsule, sacheier, paper, oranother container. In case of functioning a carrier as a diluent, thecarrier is a solid, semi-solid, or liquid material which functions as amedium. Accordingly, a formulation according to the present inventionmay be produced in the form of tablet, pill, powder medicine, intraoralmedicine, elixir agent, suspending agent, emulsifier, dissolving agent,syrup agent, aerosol agent (solid in liquid medium), and ointment. Sucha formulation may contain up to 10% of an active compound. It ispreferred to formulate a compound having activities for the treatment orprevention of hepatocirrhosis prior to administration.

[0101] Any suitable carrier well known to those skilled in the art maybe used for the formulation. In such formulation, a carrier is in theform of solid, liquid, or a mixture thereof. For instance, a compoundhaving type-X sPLA₂ inhibitory activities is dissolved into 4%dextrose/0.5% sodium citrate aqueous solution so as to be 2 mg/mLconcentration for intravenous injection. Solid formulation includespowder, tablet, and capsule. Solid carrier consists of one or more ofmaterial(s) for serving also as fragrant, lubricant, dissolving agent,suspension, binder, tablet disintegrator, capsule. A tablet for oraladministration contains a suitable excipient such as calcium carbonate,sodium carbonate, lactose, calcium phosphate and the like together witha disintegrator such as corn starch, alginic acid and the like and/or abinder such as gelatin, acacia and the like, and a lubricant such asmagnesium stearate, stearic acid, talc and the like.

[0102] In a powder medicine, a carrier is a finely pulverized solidwhich is blended with finely pulverized active ingredients. In a tablet,active ingredients are admixed with a carrier having required bindingpower in a suitable ratio, and it is solidified in a desired shape andsize. Powder medicine and tablet contain about 1 to about 99% by weightof the active ingredients being novel compounds according to the presentinvention. An example of suitable solid carriers includes magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth gum, methyl cellulose, sodiumcarboxymethylcellulose, low-melting wax, and cocoa butter.

[0103] An axenic liquid formulation contains suspending agent,emulsifier, syrup agent, and elixir agent. Active ingredients may bedissolved or suspended into a pharmaceutically acceptable carrier suchas sterile water, a sterile organic solvent, a mixture thereof and thelike. Active ingredients may be dissolved frequently into a suitableorganic solvent such as propylene glycol aqueous solution. When finelypulverized active ingredients are dispersed into aqueous starch, sodiumcarboxymethylcellulose solution, or suitable oil, the other compositionscan be prepared.

[0104] The dosage varies with the conditions of the disease,administration route, age and body weight of patient. In the case ofintravenous administration, the dosage can generally be between 0.01 to10 mg/kg/h for adult, preferably 0.1 to 1 mg/kg/h.

EXAMPLE Example 1 Preparation of cells expressing human type-X sPLA₂ andtheir culture supernatants

[0105] cDNA sequence encoding human type-X sPLA₂ (Cupillard et al., J.Biol. Chem, 1997, 272, 15745-15752) was inserted into the downstreamregion of the promoter of pSVL SV40 Late Promoter Expression Vector(Amersham Pharmacia Biotech Inc.) that is an expression vector formammalian cells. The obtained expression vector was transfected into thehost CHO cells with a LipofectAMINE reagent (Gibco BRL Inc.) accordingto the manufacture's instruction to obtain the CHO cells stablyexpressing human type-X sPLA₂. The transfected cell was cultured inα-MEM medium containing 10% fetal calf serum for 3 days and its culturesupernatant was used for the measurement of each enzyme activity.

Example 2 Inhibition Test

[0106] In order to identify and evaluate an inhibitor of type-X sPLA₂,the following chromogenic assay is utilized. This assay has been appliedfor high volume screening using a 96-well microtiterplate. A generalexplanation for this assay is described in “Analysis of Human SynovialFluid Phospholipase A₂ on Short Chain Phosphatidylcholine-MixedMicelles: Development of a Spectrophotometric Assay Suitable for aMicortiterplate Reader” (Analytical Biochemistry, 204, pp 190-197, 1992by Laure. J. Reynolds. Lori L. Hughes and Edward A. Dennis.

[0107] Test compounds (or solvent blank) were added according to thealignment of plates that had been previously set. Human type-X sPLA₂ wasincubated (30 min at 40° C. (15 μl/well)) with diheptanoylthio PC (1 mM)in the presence of Triton X-100 (0.3 mM) and5,5′-dithiobis(2-nitrobenzoic acid) (125 μM) in Tris-HCl buffer (25 mM,pH 7.5) containing CaCl₂ (10 mM), KCl (100 mM), and bovine serum albumin(1.0 mg/mL). The changes in the absorbance at 405 nm were measured andthe inhibition activities were calculated.

[0108] The IC₅₀ value was determined by plotting the log concentrationof the above-mentioned compounds (1)-(19) with respect to theirinhibition values within 10% to 90% inhibitory range.

[0109] Results of the type-X sPLA₂ inhibition test is shown in thefollowing Table 1. TABLE 1 Compound Compound No. IC₅₀(nM) No. IC₅₀(nM) 110 11 10 2 10 12 16 3 5 13 19 4 27 14 9 5 12 15 17 6 17 16 7 7 5 17 12 83 18 16 9 13 19 26 10 12

Example 3 Immunohistochemical Analysis in Human Hepatocirrhosis Tissueswith Anti-Type-X sPLA₂ Antibody

[0110] In this experiment, anti-type-X sPLA₂ antibody which wasdescribed in “The Journal of Biological Chemistry Vol. 274, No. 48,pp.34203-34211 1999” was used. Paraffin embedded preparations of humanliver cirrhosis tissues and corresponding normal tissues were purchasedfrom Biochain Inc. (San Leandro, Calif.). The tissue sections in theslides were dewaxed, treated in methanol containing 0.3% H₂O₂ for 30 minto remove the endogenous peroxidase activity and incubated with 5%normal goat serum for 20 min. The slides were then incubated withanti-type sPLA₂ antibody (6 μg/mL) in PBS containing 0.1% bovine serumalbumin for 14 hr at 4° C. After washing with PBS, they were incubatedwith biotin-conjugated goat anti-rabbit IgG antibody for 30 min followedby treatment with peroxidase labelled avidin-biotin complex reagent(Vector Laboratories). After washing, the samples were processed with200 μg/ml diaminobenzidine hydrochloride substrate dissolved in 50mmol/L Tris HCl (pH 7.6) containing 0.006% H₂O₂ for 10 min resulting inthe appearance of color dependent on the peroxidase activity tovisualize the type-X sPLA₂ expression in the tissue preparations. Inaddition, the nuclei were counterstained with 0.4% hematoxylin solution.Positive signals representative for type-X sPLA₂ expression wasvisualized as a dark-brownish color of diaminobenzidine deposit. Theneutralization of type-X sPLA₂ specific signals was conducted byincubating anti-type-X sPLA₂ antibody with purified type-X sPLA₂ protein(60 μg/ml) for 2 hr before the addition to the slides.

[0111] Consequently, positive signals representative for type-X sPLA₂expression were weakly observed in hepatic lobule and Kupffer'ssatellate cells in normal human liver tissues. In contrast, the positivesignals were strongly detected in the hepatocytes of pseudolobule in theliver prepared from patients of hepatocirrhosis. Since the addition oftype-X sPLA₂ protein resulted in abolishment of the signals, they wereverified as the specific signals for type-X sPLA₂. In addition, therewas no positive signal when IgG prepared from non-immunized rabbit wasused. Taken together, these findings suggest that the expression oftype-X sPLA₂ protein was greatly elevated in human liver cirrhosistissues.

FORMULATION EXAMPLE

[0112] It is to be noted that the following Formulation Examples 1 to 8are mere illustration, but not intended to limit the scope of theinvention. The term “active ingredient” means the compounds having ananti-hepatocirrhosis activity, the prodrugs thereof, theirpharmaceutical acceptable salts, or their hydrate.

Formulation Example 1

[0113] Hard gelatin capsules are prepared using of the followingingredients: Dose (mg/capsule) Active ingredient 250 Starch, dried 200Magnesium stearate 10 Total 460 mg

Formulation Example 2

[0114] A tablet is prepared using of the following ingredients: Dose(mg/tablet) Active ingredient 250 Cellulose, microcrystals 400 Silicondioxide, fumed 10 Stearic acid 5 Total 665 mg

[0115] The components are blended and compressed to form tablets eachweighing 665 mg.

Formulation Example 3

[0116] An aerosol solution is prepared containing the followingcomponents: Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22(chlorodifluoromethane) 74.00 Total 100.00

[0117] The active compound is mixed with ethanol and the admixture addedto a portion of the propellant 22, cooled to −30° C. and transferred tofilling device. The required amount is then fed to stainless steelcontainer and diluted with the reminder of the propellant. The valveunits are then fitted to the container.

Formulation Example 4

[0118] Tablets, each containing 60 mg of active ingredient, are made asfollows. Active ingredient 60 mg Starch 45 mg Microcrystals cellulose 35mg Polyvinylpyrrolidone 4 mg (as 10% solution in water) Sodiumcarboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total150 mg

[0119] The active ingredient, starch, and cellulose are passed through aNo. 45 mesh U.S. sieve, and the mixed thoroughly. The aqueous solutioncontaining polyvinylpyrrolidone is mixed with the resultant powder, andthe admixture then is passed through a No. 14 mesh U.S. sieve. Thegranules so produced are dried at 50° C. and passed through a No. 18mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate,and talc, previously passed through No. 60 mesh U.S. sieve, are thenadded to the granules which, after mixing, are compressed on a tabletmachine to yield tablets each weighing 150 mg.

Formulation Example 5

[0120] Capsules, each containing 80 mg of active ingredient, are made asfollows: Active ingredient 80 mg Starch 59 mg Microcrystals cellulose 59mg Magnesium stearate 2 mg Total 200 mg

[0121] The active ingredient, cellulose, starch, and magnesium stearateare blended, passed through a No. 45 mesh U.S. sieve, and filled intohard gelatin capsules in 200 mg quantities.

Formulation Example 6

[0122] Suppository, each containing 225 mg of active ingredient, aremade as follows: Active ingredient 225 mg Saturated fatty acidglycerides 2000 mg Total 2225 mg

[0123] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation Example 7

[0124] Suspensions, each containing 50 mg of active ingredient per 5 mLdose, are made as follows: Active ingredient 50 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 mL Benzoic acid solution 0.10 mL Flavor q.v.Color q.v. Purified water to total 5 mL

[0125] The active ingredient is passed through a No. 45 U.S. sieve, andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution and flavor are diluted with a portionof the water and added, with stirring. Sufficient water is then added toproduce the required volume.

Formulation Example 8

[0126] An intravenous formulation may be prepared as follows: Activeingredient 100 mg Saturated fatty acid glycerides 1000 mL

[0127] The solution of the above ingredients generally is administeredintravenously to a subject at a rate of 1 mL per minute.

INDUSTRIAL APPLICABILITY It is provided that type-X sPLA₂ inhibitors areuseful in preventing or treating hepatocirrhosis.

1. A composition for prevention or treatment of hepatocirrhosis whichcontains a type-X sPLA₂ inhibitor as an active ingredient.
 2. Acomposition for prevention or treatment of hepatocirrhosis whichcontains as an active ingredient a compound represented by the formula(I):

wherein ring a is represented by the formula (a) to (d):

wherein R¹ and R² are each independently hydrogen atom, non-interferingsubstituent, or -(L¹)-(acidic group) wherein L¹ is an acid linker havingan acid linker length of 1 to 5, provided that one of the R¹ and R² is-(L¹)-(acidic group); R³ and R⁴ are each independently hydrogen atom,non-interfering substituent, carbocyclic group, carbocyclic groupsubstituted with a non-interfering substituent(s), heterocyclic group,or heterocyclic group substituted by a non-interfering substituent(s);and —B— is represented by the formula (e) to (h):

 wherein R⁵ is (j) C1 to C20 alkyl, C2 to C20 alkenyl, C2 to C20alkynyl, carbocyclic group, or heterocyclic group, (k) the grouprepresented by (j) each substituted independently with at least onegroup selected from non-interfering substituents, or -(L²)-R⁸ wherein L²is a divalent linking group of 1 to 18 atom(s) selected from hydrogenatom(s), nitrogen atom(s), carbon atom(s), oxygen atom(s), and sulfuratom(s), and R⁸ is a group selected from the groups (j) and (k); R⁶ ishydrogen atom, halogen, C1 to C3 alkyl, C3 to C4 cycloalkyl, C3 to C4cycloalkenyl, C1 to C3 alkyloxy, or C1 to C3 alkylthio; R⁷ is hydrogenatom or non-interfering substituent; R^(A) is represented by theformula:

 wherein R⁹ and R¹⁰ are each independently hydrogen atom, C1 to C3alkyl, or halogen; X and Y are each independently oxygen atom or sulfuratom; and Z is —NH₂ or —NHNH₂; R^(B) is —CONH₂ or —CONHNH₂; and, Ring Dis cyclohexene ring or benzene ring;  provided that Ring A is (b), (c),or (d) when —B— is (e) or (f),  a prodrug thereof, its pharmaceuticallyacceptable salt, or its solvate.
 3. A composition for prevention ortreatment of hepatocirrhosis which contains a compound, a prodrugthereof, its pharmaceutically acceptable salt, or its solvate as claimedin claim 2 as an active ingredient, wherein R¹ is hydrogen atom or-(L³)—R¹” wherein L³ is —OCH₂—, —SCH₂—, —NH—CH₂—, —CH₂—CH₂—,—O—CH(CH₃)—, or —O—CH(CH₂CH₂C₆H₅)—; R¹¹ is —COOH, —CONHSO₂C₆H₅, —SO₃H,or —P(O)(OH)₂; and R² is hydrogen atom or -(L⁴)-R¹² wherein L⁴ isrepresented by the formula:

 wherein R¹³ and R¹⁴ are each independently hydrogen atom, C1 to C10alkyl, C1 to C10 aralkyl, carboxy, alkyloxycarbonyl, or halogen; R!² is—COOH, —SO₃H, or —P(O)(OH)₂, provided R¹ and R² are not hydrogen atom atthe same time.
 4. A composition for prevention or treatment ofhepatocirrhosis which contains a compound, a prodrug thereof, itspharmaceutically acceptable salt, or its solvate as claimed in claim 2as an active ingredient, wherein R³ is hydrogen atom, C1 to C6 alkyl, C3to C6 cycloalkyl, aryl, or a heterocyclic group and R⁴ is hydrogen atomor halogen.
 5. A composition for prevention or treatment ofhepatocirrhosis which contains a compound, a prodrug thereof, itspharmaceutically acceptable salt, or its solvate as claimed in claim 2as an active ingredient, wherein R⁵ is —(CH₂)₁₋₆—R¹⁵ wherein R¹⁵ isrepresented by the formula:

wherein b, d, f, h, j, m, and o are independently an integer from 0 to2; R¹⁶ and R¹⁷ are each independently halogen, C1 to C10 alkyl, C1 toC10 alkyloxy, C1 to C10 alkylthio, aryloxy, or C1 to C10 haloalkyl; α isoxygen atom or sulfur atom; β is —CH₂— or —(CH₂)₂—; γ is oxygen atom orsulfur atom; c, i, and p are independently an integer from 0 to 5; e isan integer from 0 to 7; g is an integer from 0 to 4; k and n are eachindependently an integer from 0 to
 3. 6. A composition for prevention ortreatment of hepatocirrhosis which contains a compound, a prodrugthereof, its pharmaceutically acceptable salt, or its solvate as claimedin claim 5 as an active ingredient, wherein R⁵ is —CH₂—R¹⁸ wherein R¹⁸is represented by the formula:

wherein β is —CH₂— or —(CH₂)₂—; R¹⁹ is hydrogen atom, C1 to C3 alkyl, orhalogen; E is a bond, —CH₂— or —O—.
 7. A composition for prevention ortreatment of hepatocirrhosis which contains a compound, a prodrugthereof, its pharmaceutically acceptable salt, or its solvate as claimedin claim 2 as an active ingredient, wherein R¹ is —OCH₂COOH.
 8. Acomposition for prevention or treatment of hepatocirrhosis whichcontains a compound, a prodrug thereof, its pharmaceutically acceptablesalt, or its solvate as claimed in claim 2 as an active ingredient,wherein R² is hydrogen atom.
 9. A composition for prevention ortreatment of hepatocirrhosis which contains a compound, a prodrugthereof, its pharmaceutically acceptable salt, or its solvate as claimedin claim 2 as an active ingredient, wherein R⁶ is C1 to C3 alkyl.
 10. Acomposition for prevention or treatment of hepatocirrhosis whichcontains a compound, a prodrug thereof, its pharmaceutically acceptablesalt, or its solvate as claimed in claim 2 as an active ingredient,wherein R^(A) is —CH₂CONH₂ or —COCONH₂.
 11. A composition for preventionor treatment of hepatocirrhosis which contains a compound as an activeingredient represented by the formula:

a prodrug thereof, its pharmaceutically acceptable salt, or its solvate.12. Use of a type-X sPLA₂ inhibitor for the preparation of a medicamentfor the treatment of hepatocirrhosis.
 13. Use as claimed in claim 12wherein the type-X sPLA₂ inhibitor is the compound claimed in any one ofclaims 2 to
 11. 14. A method of treating a mammal, including a human, toalleviate the pathological effects of hepatocirrhosis, which comprisesadministration to said mammal of a type-X sPLA₂ inhibitor in apharmaceutically effective amount.
 15. A method as claimed in claim 14wherein the type-X sPLA₂ inhibitor is the compound claimed in any one ofclaims 2 to 11.